The deleterious mutation load is insensitive to recent population history.
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Human populations have undergone major changes in population size in the past 100,000 years, including recent rapid growth. How these demographic events have affected the burden of deleterious mutations in individuals and the frequencies of disease mutations in populations remains unclear. We use population genetic models to show that recent human demography has probably had little impact on the average burden of deleterious mutations. This prediction is supported by two exome sequence data sets showing that individuals of west African and European ancestry carry very similar burdens of damaging mutations. We further show that for many diseases, rare alleles are unlikely to contribute a large fraction of the heritable variation, and therefore the impact of recent growth is likely to be modest. However, for those diseases that have a direct impact on fitness, strongly deleterious rare mutations probably do have an important role, and recent growth will have increased their impact.
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In a population with larger Ne, the efficacy of purifying selection against recessive alleles increases proportional to Ne^1/2, but mutational input increases proportional to Ne, so at equilibrium an individual in a larger-Ne population has a greater expected number of recessive lethal mutations.
“In a population with larger N e, the efficacy of purifying selection against recessive alleles increases (proportional to N e 1 = 2 ), but the increase in the mutational input (proportional to N e) is greater than the increase in the efficacy of selection (Simons et al. 2014). Therefore, at equilibrium, an individual in a population with larger N e will have a greater expected number of recessive”
From An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans (2015) · cites this paper as Simons et al. 2014
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Experimental — accuracy not yet measuredA related computation of the overall influence of natural selection in human history, relying on measures of selection against deleterious variants rather than directional selection of favorable variants, does not suggest strong systematic differences in the magnitude of selection among different continental population groups.
“However, a related computation of the overall influence of natural selection in human history, relying on measures of selection against deleterious variants rather than directional selection of favorable variants, does not suggest strong systematic differences in the magnitude of selection among different continental population groups [50–52]”
From Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences (2019) · cites this paper as [51]
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Self-citationEvolutionary Genomics of Structural Variation in Asian Rice ( Oryza sativa ) Domestication
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The Limits of Natural Selection in a Nonequilibrium World
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Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences
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“population groups [50-52]; indeed, some researchers have argued for a greater level of deleterious variation in non-Africans rather than in Africans [50,52], a pattern opposite to what might be expected”
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Accumulation of Deleterious Mutations During Bacterial Range Expansions
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The Role of Deleterious Substitutions in Crop Genomes
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Purging of deleterious burden in the endangered Iberian lynx
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Trait Evolution in Invasive Species
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Recombination affects accumulation of damaging and disease-associated mutations in human populations
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Range Expansion Compromises Adaptive Evolution in an Outcrossing Plant
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Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck
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Purging of highly deleterious mutations through severe bottlenecks in Alpine ibexPreprint
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Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans
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Self-citationHuman demographic history has amplified the effects of background selection across the genome
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Evolutionary perspectives on polygenic selection, missing heritability, and GWAS
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Self-citation
- Authors
- Simons, Y. B., Turchin, M. C., Pritchard, J. K., & Sella, G.
- Affiliations
- Hebrew University of Jerusalem (IL)
- University of Chicago (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Pritchard, Jonathan K
- Sella, Guy
- Venue
- Nature Genetics
- Published
- 2014-02-09
- Volume
- 46
- Issue
- 3
- Pages
- 220-224
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3953611
- OpenAlex
- W1994975196
- Cited by
- 279
- References
- 30
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 12 · 2023: 17 · 2022: 16 · 2021: 26 · 2020: 12 · 2019: 26 · 2018: 34 · 2017: 26 · 2016: 28 · 2015: 34 · 2014: 20 · 2013: 5
- FWCI
- 23.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- arXiv (Cornell University) (submittedVersion)
- arXiv (Cornell University)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Mental Health (R01MH084703, MH084703)
- National Institute of General Medical Sciences (R01GM083228, GM083228, T32GM007197)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- deleterious mutation load, population growth, population size change, exome sequencing, pathogenic variants, rare alleles, heritable variation, fitness effects of mutations, West African ancestry, European ancestry, population genetic models
- MeSH terms
- Genetics, Population, Humans, Models, Genetic, Mutation, Population Dynamics, Polymorphism, Single Nucleotide, Genetic Load, Black People, White People, Exome
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